This proposal has as its objective an investigation of control of growth and DNA replication in normal and neoplastic tissues. Four major approaches will be used. First, we intend to purify and characterize DNA polymerases present in the nucleus. Activities as well as physical properties of the DNA polymerases from liver nuclei and hepatoma nuclei will be compared. Any differences observed between the two tissues will be investigated in a fast growing, an intermediate growing and a slow growing hepatoma. Secondly, we intend to identify, separate and hopefully reconstruct nuclear components that make up a replicating complex. It is by now obvious that factors other than DNA and DNA polymerase must be part of the replicating system. We will look for such factors in nuclei and investigate their possible significance in the control of DNA replication. Thirdly, we will use bleomycin to investigate possible differences in DNA repair in liver and hepatoma cells. Bleomycin stimulates 3H-TTP incorporation in a nuclear incorporating system. Stimulation of host liver nuclei is much more dramatic than stimulation of hepatoma nuclei. The possibility that this difference is due to a less efficient repair system in hepatomas will be explored. Fourthly, the effect of cytoplasmic or humoral factors on DNA replication will be investigated. There is evidence that such factors play a role in control of growth and DNA synthesis. By using factors from hepatoma tissues or tumor-bearing animals on nuclei or cells of liver, or factors from normal animals on nuclei or cells from hepatomas, we hope to obtain evidence that such factors might influence the loss of control in neoplastic cells.